Since the discovery of the cytotoxic activity of cisplatin in 1964, decades have been spent investigating the antitumor activity of platinum complexes. At the moment, cisplatin and its derivatives carboplatin and oxaliplatin belong to the most famous metal-based anticancer agents.1 
Although very efficient, these cytostatic platinum complexes have severe drawbacks. First, resistance can occur, which is either intrinsic or acquired. Second, its antitumor activity is limited to only several tumor types. Third, the platinum complexes have a high general toxicity leading to negative side effects, including but not limited to kidney damage.
Although platinum anticancer agents are still the most commonly used metal-based anticancer drugs, their drawbacks have led scientists to investigate complexes of other platinum group metals, such as ruthenium. Ruthenium complexes with high cytotoxic activity can be divided into three classes. The first class contains the NAMI-based compounds.
The second class are the organometallic half-sandwich compounds with the formula [Ru(η6-arene)(diamine)(Cl)]. The third class of compounds, which will be discussed in more detail, are ruthenium compounds with polypyridyl ligands.
Ruthenium complexes are thought to interact with biological ligands, and notably DNA. Since the ruthenium complexes have an octahedral instead of a square planar geometry, the binding modes to DNA probably differ from those of cytostatic platinum complexes. Furthermore, it has been shown that DNA is not the only target of several cytostatic ruthenium complexes, but that plasma proteins also bind to the metal centre.
One of the mechanisms of action of ruthenium-based anticancer compounds is thermal formation of an aqua ruthenium complex, which binds to DNA and proteins. Like for cisplatin DNA is one target of antitumor-active ruthenium complexes, but ruthenium-protein interactions play a significant role as well. (Messori, L.; Orioli, P.; Vullo, D., Eur. J. Biochem. 2000, 267, 1206; Ho, M.-Y.; Chiou, M.-L.; Du, W.-S.; Chang, F. Y.; Chen, Y.-H.; Weng, Y.-J.; Cheng, C.-C., J. Inorg. Biochem. 2011, 105, 902). Whatever the final target might be, the main mechanism of action of ruthenium-based anticancer drugs containing chloride ligands bound to the ruthenium center, [Ru—Cl], comprises: 1) hydrolysis of the metal-chloride bond, to give the aqua complex [Ru—OH2], followed by 2) binding of the aqua complex to a biological target, to give a DNA- or protein-bound species; and finally 3) apoptosis triggered by these ruthenium adducts. Although hydrolysis of the Ru—Cl bond occurs faster inside the cells due to the lower cytoplasmic chloride concentration, it is a thermal process that can occur anywhere, which is one of the reasons for the general toxicity of ruthenium-based drugs.
Two examples of polypyridyl ruthenium compounds which show high cytostatic activity are mer-[Ru(terpy)(Cl)3]2 and α-[Ru(azpy)2(Cl)2]3 Another known and interesting anticancer agent is [Ru(terpy)(apy)(Cl)](Cl).4 It is believed that this compound is converted into the cationic active form [Ru(terpy)(apy)(H2O)]2+ in the body by thermal cleavage of the coordination bond between the ruthenium and the chlorine atoms. The structure of the biologically active form of this complex is shown below

Since human body temperature is 37° C., the anticancer agent [Ru(terpy)(apy)(H2O)]2+ might be released anywhere in the body when [Ru(terpy)(apy)(Cl)](Cl) is used as a drug. This affects both healthy and tumor cells. Naturally an effect on healthy cells by a cytostatic agent causes unwanted side effects.
In addition, some of the biologically active polypyridyl ruthenium compounds, such as mer-[Ru(terpy)(Cl)3] or α-[Ru(azpy)2(Cl)2], are poorly soluble in water, which limits their pharmaceutical use.
Tumor irradiation in vivo is clinically employed during photodynamic therapy (PDT). PDT consists in the administration of a photosensitizer (generally a porphyrin or phthalocyanine compound), followed by the non-invasive irradiation of the tumor(s) with light (Brown, S. B.; Brown, E. A.; Walker, I., Lancet Oncol. 2004, 5, 497). The photosensitizer is non-toxic in the dark, but in presence of oxygen and light it produces a significant amount of highly toxic, short-lived radical species, culminating in cell death via irreversible damage to cellular components such as proteins, lipids, and DNA.
Overall, using light to activate anticancer prodrugs is attractive in anticancer therapy as it is poorly invasive, spatially accurate, and as it can reach places where surgery is impossible. Of course drug activation by light is particularly suited for skin, lung, or digestive track cancers, for which a source of light can easily be directed onto the tumor. However, it is also possible to shine light on internal organs using endoscopy, to cure prostate, head and neck, bile duct, or bladder cancers for example. Several photosensitizers for PDT have been clinically approved, so that light irradiation techniques are now available within hospitals.
PDT is selective and highly effective in certain cancers. However, there are PDT-resistant tumors as well. The selectivity of PDT is high because: 1) the photosensitizer accumulates in tumor tissues; 2) the photochemically generated radical species are highly reactive, which limits oxidative damage to the vicinity of the photosensitizer; and 3) only the tumor is irradiated, which physically confines the photodynamic action to tumor tissues. Due to its selectivity, toxicity and patient discomfort are kept to a minimum, while PDT has proven to be highly efficacious in the treatment of various cancer types. However, several cancers, including recurrent superficial bladder cancer, non-resectable cholangiocarcinomas, and certain head-and-neck and esophageal cancers, respond poorly to PDT (Nseyo, U. O.; DeHaven, J.; Dougherty, T. J.; Potter, W. R.; Merrill, D. L.; Lundahl, S. L.; Lamm, D. L., J. Clin. Laser Med. Surg. 1998, 16, 61).
One of the reasons of such recalcitrance is the poor oxygenation of tumor tissues (Coleman, C. N., J. Natl. Cancer Inst. 1988, 80, 310; Mellor, H.; Snelling, S.; Hall, M.; Mdok, S.; Jaffar, M.; Hambley, T.; Callaghan, R., Biochem. Pharmacol. 2005, 70, 1137) which is a consequence of their poor vasculature and high demand in energy.
It is an object of the present invention to obviate and/or mitigate one or more of the aforementioned disadvantages.
It is an object of the present invention to provide ruthenium-based compounds, which are initially biologically inactive (or biologically inactive to a limited extent only) and that can be activated in due course through the influence of light to become biologically active or more biologically active.